Abstract Myelodysplastic syndromes (MDS) are part of a heterogeneous and overlapping group of clonal diseases that arise in the hematopoietic stem or progenitor cells and also include acute myeloid leukemia (AML), myeloproliferative neoplasms (MPN), and the hybrid MDS/MPN entities. Individuals with MDS have a high risk of progressing to leukemia, with approximately 30% expected to develop AML. Outcomes for MDS are poor, with 5 year relative survival estimates below 50%, suggesting that early detection and prevention could have a large impact. During our initial funding period, we conducted the first population-based case control study of MDS, including recruitment of over 550 cases. In this competing renewal application, we propose to capitalize on our well-characterized study population to investigate the contribution of genetic variation to MDS risk and to evaluate the role of the killer cell immunoglobulin receptors (KIR) on incidence and survival. Our specific aims are to: 1) Identify germline susceptibility variants for MDS through collaboration with the MDS Clinical Research Consortium; 2) Evaluate the relationship between KIR haplotypes and risk of MDS; and 3) Understand the role of KIR gene haplotypes in disease progression and survival, overall and by MDS subtype. We hypothesize that we will identify variants that predict MDS risk and that risk estimates will be larger in cases with high risk MDS subtypes who are more likely to progress to AML. We further hypothesize that KIR haplotype B will be identified at a lower frequency in MDS cases compared with population controls and that KIR haplotype A will be associated with worse prognosis. We will genotype germline DNA samples from 465 MDS cases from our case-control study, 200 MDS cases from Moffitt Cancer Center and 1,119 age- matched population controls using the Illumina HumanOmni2.5 array. We will use available genotyping data from 1,700 MDS cases from the MDS Clinical Research Consortium and 4,597 healthy controls for replication and meta-analysis. In order to improve our power to detect associations, we will restrict our analysis to regions of open chromatin in myeloid cells as determined by ATAC-seq of primary cell cultures. For Aim 2, targeted capture and sequencing will be used to measure variation in the 143kb region containing the KIR genes on chromosome 19 (position 5537984-55378670). We will compare the two main KIR gene haplotype blocks (A and B) in cases and controls. To evaluate the impact of KIR haplotypes on progression, we will treat the 457 confirmed MDS cases as a cohort and evaluate associations between KIR haplotype and progression to AML and survival. The role of common genetic variation is largely unexplored in MDS; however, the few studies that have been conducted provide a rationale for further evaluation. Identifying predictors of rapid death from MDS, such as KIR haplotypes or alleles, could provide clues to the underlying biology in this subgroup and suggest new avenues for therapy. Adoptive NK cell therapy is one such option that is already in development for treatment of hematologic malignancy.